The present invention relates to pyrimidine derivatives and medicinal uses thereof. In more detail the present invention relates to pyrimidine derivatives having activities for suppression of type 2 helper T cell (Th2) immune responses and enhancement of type 1 helper T cell (Th1) immune responses and therapeutic methods for immune diseases by using the pyrimidine derivatives and therapeutic compositions containing the pyrimidine derivatives.
It is first proposed by Mosmann et al. that Lymphocytes, called helper T cells which play the central role in immune responses are classified into two subsets. They classified mouse helper T cells (Th) into Th1 and Th2 depending on the kinds of cytokines produced (J. Immunol. 136, 2348-2357 (1986)).
As Th1-type cytokines, interleukin 2 (IL-2), interferon xcex3 (IFN-xcex3), etc. are illustrated. As Th2-type cytokines, interleukin 4 (IL-4), interleukin 5 (IL-5), interleukin 10 (IL-10), interleukin 13 (IL-13), etc. are illustrated.
Nowadays thinking of the classification into Th1/Th2 is applied to the classification of helper T cell subsets, and also regarding a variety of immune responses in the living body on the point of view of which subset of helper T cells mainly participates, the immune responses have become to be interpreted xe2x80x9cimmune responses on Thl-typexe2x80x9d or xe2x80x9cimmune responses on Th2-typexe2x80x9d, respectively.
Immune responses on Th1-type are mainly induced by cytokines such as interleukin 2 (IL-2), interferon xcex3 (IFN-xcex3), etc. produced by activated Th1. Thus, it is known that Th1 cytokines participate to cell-mediated immunity such as protection mainly against infections of virus, bacteria, etc. by activation of macrophage, natural killer cells etc., or by further activation of Th1 via IL-12 etc. produced by the activated macrophages.
On the other hand, immune responses on Th2-type are mainly induced by cytokines such as IL-4, IL-5, etc. produced by activated Th2. Thus, it is known that Th2 cytokines participate to humoral immunity such as production of antibodies (e.g. IgE class) from B cells.
Since Th2 produce cytokines such as IL-4 or IL-5 which relates to allergic reaction, as mentioned below, Th2 are suggested to be the responsible cells on allergic reaction. For example, IL-4, a typical Th2-type cytokine, intduces production of IgE antibodies from B cells. IL-4 also induces expression of VCAM-1 gene, which is an important molecule which works when eosinophils adhere to vascular endothelial cells and infiltrate into the tissue (Farumashia, 29, 1123-1128(1993)). Recently IL-4 has been paid attention as a differentiation-inducing factor for Th2. IL-5, another Th2-type cytokine, induces differentiation, migration and activation of eosinophils. Allergic inflammation is characterized in being triggered off by infiltration, activation and degranulation of eosinophils, as typical chronic airway inflammation in asthma. Thus IL-5 is considered to be a factor inducing allergic inflammation.
Since Th2 cytokines have above properties, it is recognized that Th2 control both allergic reactions of xe2x80x9cearly phase reactionxe2x80x9d by IgE antibodies or mast cells and xe2x80x9clate phase reactionxe2x80x9d by eosinophils, and therefore, Th2 are central cells in allergic inflammation. And it is considered that allergic diseases are caused by over expression of Th2-type immune responses. This consideration is also supported by findings of presence of Th2 or production of Th2-type cytokines such as IL-4, IL-5, etc. in the lesion of allergic disease, such as airway or skin.
Therefore, it is considered to be important to suppress immune responses of Th2, in order to inhibit both ealy phase and late phase reactions, or inhibit allergic inflammatory reaction characterized with infiltration and activation of eosinophils in the stage of fundamental source and to treat therapeutically and prophylactically general allergic diseases. Namely, if a drug is developed to suppress immune responses of Th2-type, the drug will be one for therapeutic and prophylactic agent for allergic diseases.
In especially serious chronic asthma or atopic dermatitis among allergic diseases, late phase reaction is considered to play an important role. However, anti-allergic agents used nowadays are mainly based on anti-histamine activity and inhibit only early phase reaction and clinical effect thereof is not satisfactory. From such viewpoints too, it has been desired to develop the drug which inhibits both early phase and late phase reactions by suppressing immune responses of Th2 and treats therapeutically and prophylactically for general allergic diseases as mentioned above.
Moreover, bronchodilators, which are represented by xanthine derivatives or xcex2-stimulants which have been used as asthma agents for long years, are known to have suppressive activity of constriction of broncho smooth muscle by various stimulation. However, these are ineffective to chronic airway inflammation which is a basic cause for asthma. In addition, side effects of xanthine derivatives or xcex2-stimulants to circulatory organs are anxious. In recent asthma therapy, as definitely shown in the guide line of WHO, asthma is taken as chronic inflammation of airway and it has made a principal object to cure the chronic inflammation of air way. The chronic inflammation of airway in asthma is triggered off by infiltration, activation and degranulation of eosinophils and has its pathologic characteristic feature which results in hypertrophy and fibrillation of airway-epithelium. According to the above guide line, the sole steroid inhalants effective to the chronic air way inflammation are now positioned as the first chosen medicine to asthma of more than middle degree.
As a result, steroids have been often used for serious asthma and atopic dermatitis as being considered as the sole effective drugs. However, it becomes problem that by using such steroids for long terms various side effects (steroid dermatitis, induced infected disease, discorticism, etc.) occur.
From the point of these views too, it has been desired to develop the drug which selectively suppresses immune responses on Th2 and inhibits both early phase and late phase reactions, or inhibits allergic inflammatory reaction characterized with infiltration and activation of eosinophils in the stage of fundamental source and is therapeutically and prophylactically effective for general allergic diseases.
Furthermore, when it is planned to develop the therapeutic or prophylactic drugs which have less side effects, it seems that the drugs which suppress immune responses on Th2 as mentioned above and enhance immune responses on Th1 simultaneously, are more preferable as medicines. As mentioned above, since Th1 play an important role for the living body, namely infection-protection against virus and bacteria by mainly producing IFN-xcex3, the drugs which suppress the immune responses on Th2 and enhance activity of Th1 are very preferable in view of side-effects. For example, immunosuppressives, e.g. cyclosporin or FK506 are known to strongly inhibit activation of Th2. However, both cyclosporin and FK506 show non-specific suppression against immune responses, namely not only inhibit activation of Th2, but also more strongly inhibit activation of Th1. Therefore, serious side effects such as opportunistic infection or increase of carcinogenic rate caused by such non-specific suppression against immune responses have been problem. Other non-specific immunosuppressives are also considered to have same problems.
As mentioned above, the drug which enhances immune responses on Th1 represented by production of IFNxcex3 and suppresses immune responses on Th2 represented by production of IL-4 and IL-5 simultaneously, will be a therapeutic and prophylactic agent for allergic diseases with less side effects.
Autoimmune diseases in the state that production of an antibody or humoral immunity are abnormally enhanced, such as systemic lupus erythematosus are also considered to be in the state that immune responses of Th2 are abnormally enhanced (Medical Immunology 15, 401 (1988)). Therefore, the drug which enhances immune responses of Th1 and suppresses immune responses of Th2 is expected to become a therapeutic agent for autoimmune diseases.
Pyrimidine derivatives having general anti-virus activity are disclosed in Japanese Patent Publication A 9-301958 and Japanese Patent Publication A8-134044. However, there is no suggestion of pyrimidine derivatives of the present invention which enhances immune responses of Th1 and suppress immune responses of Th2.
Under such circumstances the present inventors synthesized various compounds and examined them on the effect to Th1 and Th2 immune responses. As a result, it was found that certain pyrimidine derivatives enhance Th1 immune responses and suppress Th2 immune responses and therefore, change the balance of Th1/Th2 into preferable direction.
That is, the present invention relates to:
[1] a pyrimidine derivative of the formula (1) or a salt thereof; 
xe2x80x83wherein R1 is a formula (2); 
xe2x80x83{in the formula (2),
ring A is substituted or unsubstituted C3-10 cycloalkane, substituted or unsubstituted C5-10 cycloalkene, substituted or unsubstituted C7-10 bicycloalkane, or substituted or unsubstituted heterocyclic ring containing O atom or S atom as a heteroatom, and said S atom may form sulfinyl or sulfonyl together with one or two oxygen atoms, and
R4 is straight or branched C1-10 alkyl, C2-6 alkenyl, C3-6 alkinyl, C3-6 cycloalkyl, C4-10 cycloalkyl-alkyl, or OR8 (R8 is straight or branched C1-10 alkyl, C3-6 alkenyl, C3-6 alkinyl, C3-6 cycloalkyl or C4-10 cycloalkyl-alkyl)}, or a formula (3); 
xe2x80x83{in the formula (3),
R5 is straight or branched C1-10 alkyl; C2-6 alkenyl; C3-6 alkinyl; straight or branched C1-10 alkyl substituted by hydroxy, halogen atom or C1-4 alkoxy; phenyl; C3-8 cycloalkyl; a 5 to 7 membered saturated heterocyclic ring containing one or two oxygen atoms as heteroatoms; or C(=O)R9 (R9 is straight or branched C1-10 alkyl, C2-6 alkenyl, C3-6 alkinyl, C3-6 cycloalkyl, C4-10 cycloalkyl-alkyl, or OR10 (R10 is straight or branched C1-10 alkyl, C2-6 alkenyl, C3-6 alkinyl, C3-6 cycloalkyl or C4-10 cycloalkyl-alkyl)),
R6 is hydrogen atom, straight or branched C1-10 alkyl, C6-10 aryl, halogen atom, C6-10 aryl substituted by C1-4 alkoxy or C1-4 alkyl, carbamoyl, or hydroxymethyl, and
R7 is hydrogen atom, or straight or branched C1-10 alkyl},
xe2x80x83R2 is hydrogen atom, or straight or branched C1-10 alkyl, and
xe2x80x83R3 is straight or branched C1-10 alkyl; C3-6 cycloalkyl; straight or branched C1-10 alkyl substituted by C1-2 alkylcarbamoyl, C2-4 dialkylcarbamoyl, C1-4 alkoxy, C1-4 alkoxycarbonyl, C3-6 cycloalkyl, hydroxy, C1-4 alkylcarbonyloxy, halogen atom, amino, C2-4 acyl-substituted amino, C1-4 alkyl-substituted sulfonylamino or C1-5 alkoxycarbonylamino; or a formula (4);
R11xe2x80x94(CH2)nxe2x80x94xe2x80x83xe2x80x83(4)
{in the formula (4), R11 is phenyl, pyridyl, thienyl, or furyl and each of them may be substituted by one or more substituents. Said substituents are halogen atom, cyano, carbamoyl, C1-4 alkoxy, or C1-4 alkyl. n is integers of 0-4, provided that n is intergers of 1-4 when R11 is phenyl.}, or
xe2x80x83R2 and R3 taken together are C3-5 alkylene or said alkylene in which methylene is substituted by O atom,
[2] The pyrimidine derivative or its salt of [1], wherein R3 is straight or branched C1-10 alkyl; C3-6 cycloalkyl; or
straight or branched C1-10 alkyl substituted by C1-2 alkylcarbamoyl, C2-4 dialkylcarbamoyl, C1-4 alkoxy, C1-4 alkoxycarbonyl, C3-6 cycloalkyl, hydroxy, C1-4 alkylcarbonyloxy, halogen atom, amino, C2-4 acyl-substituted amino, C1-4 alkyl-substituted sulfonylamino or C1-5 alkoxycarbonylamino; or
xe2x80x83R2 and R3 taken together are C3-5 alkylene or said alkylene in which methylene is substituted by O atom,
[3] The pyrimidine derivative or its pharmaceutically acceptable salt of [1] or [2], wherein R2 and R3 taken together is trimethylene or tetramethylene,
[4) The pyrimidine derivative or its pharmaceutically acceptable salt of [1] or [2], wherein R3 is straight or branched C1-7 alkyl,
[5] The pyrimidine derivative or its pharmaceutically acceptable salt of [1], wherein R3 is the formula (4);
R11xe2x80x94(CH2)nxe2x80x94xe2x80x83xe2x80x83(4)
xe2x80x83wherein R11 and n are the same defined above,
[6] The pyrimidine derivative or its pharmaceutically acceptable salt of [1] or [5], wherein R11 of the formula (4) is pyridyl, thienyl or furyl,
[7] The pyrimidine derivative or its pharmaceutically acceptable salt of [1], [5] or [6], wherein n of the formula (4) is integers 2-4,
[8] The pyrimidine derivative or its pharmaceutically acceptable salt of any one of [1] to [7], wherein R1 is the formula (2); 
xe2x80x83wherein the ring A and R4 are the same defined above,
[9] The pyrimidine derivative or its pharmaceutically acceptable salt of any one of [1] to [7], wherein R1 is the formula (3); 
xe2x80x83wherein ring R5, R6 and R7 are the same defined above,
[10] The pyrimidine derivative or its pharmaceutically acceptable salt of any one of [1] to [7] or [9], wherein R5 is straight C2-4 alkyl or straight C2-4 alkyl substituted by hydroxy,
[11]. An immunomodulator which suppresses immune responses of type 2 helper T cell and enhances immune responses of type 1 helper T cell, comprising the pyrimidine derivative or its pharmaceutically acceptable salt of any one of [1] to [10] as an active ingredient,
[12] A therapeutic or prophylactic agent for diseases in the state that immune responses of type 2 helper T cell are abnormally enhanced, comprising the pyrimidine derivative or its pharmaceutically acceptable salt of any one of [1] to [10] as an active ingredient,
[13] The therapeutic or prophylactic agent of [12], wherein the disease in the state that immune responses of type 2 helper T cell are abnormally enhanced is an allergic disease, and
[14] The therapeutic or prophylactic agent of [13], wherein the allergic disease is asthma, allergic rinitis, or allergic dermatitis.
The present invention is explained in detail below.
xe2x80x9cSubstituents R1, R2 and R3xe2x80x9d on pyrimidine ring of the present invention are explained as follows:
In regard to R1,
examples of C3-10 cycloalkane in ring A are cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc. Examples of C5-10 cycloalkene are cyclopentene, cyclohexene, etc. Examples of C7-10 bicycloalkane are bicyclo[2.2.1]heptane, bicyclo[2.2.1]hepta-5-ene, bicyclo[2.2.2]octane, bicyclo[2.2.2]octa-5-ene, etc. Examples of hererocyclic ring containing O atom or S atom as a heteroatom are oxetane, thietane (trimethylenesulfide), thietane-l-oxide (trimethylenesulfoxide), thietane-1,1-dioxide (trimethylenesulfone), tetrahydrofuran, tetrahydrothiophene, tetrahydrothiophene-1-oxide, tetrahydrothiophene-1,1-dioxide, tetrahydro-4H-pyran, thian (pentamethylenesulfide), thian-1,1-dioxide (pentamethylenesulfone), thian-1-oxide (pentamethylenesulfoxide), oxepane (hexamethyleneoxide), thiepane (hexamethylenesulfide), thiepane-1-oxide (hexamethylenesulfoxide), thiepane-1,1-dioxide (hexamethylenesulfone), 7-oxabicyclo[2.2.1]heptane, 7-oxabicyclo[2.2.1]hepta-5-ene, etc., and
examples of substituents of substituted cycloalkane, substituted cycloalkene, substituted bicycloalkane and substituted heterocyclic ring in ring A are C1-3 alkyl, hydroxy, C1-3 alkoxycarbonyl, carboxy, carbamoyl, etc. And said substituents on the adjacent carbon atoms may form tetramethylene bridge, or carbon atom(s) in the ring may be substituted by carbonyl(Cxe2x95x90O). Said substituent(s) are one or more and the same or different. Examples of C1-3 alkyl are methyl, ethyl, n-propyl, 2-propyl, etc. Examples of C1-3 alkoxycarbonyl are methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, 2-propoxycarbonyl, etc.
Examples of straight or branched C1-10 alkyl in R2, R3, R4, R5, R6, R7, R8, R9 and R10 are methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl, etc.
Examples of C2-6 alkenyl in R4, R5, R8, R9 and R10 are vinyl, allyl, butenyl, pentenyl, hexenyl, etc.
Examples of C2-6 alkenyl in R4, R5, R8, R9 and R10 are propargyl, butinyl, pentinyl, etc.
Examples of C3-8 cycloalkyl in substituents of straight or branched C1lo alkyl in R3, R4, R5, R8, R9 and R10 are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.
Examples of C4-10 cycloalkyl-alkyl in R4, R8, R9 and R10 are cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylpropyl, etc.
Examples of halogen atoms in R3, R5 and R6 are fluorine atom, chlorine atom, bromine atom, or iodine atom.
Examples of C1-4 alkoxy in R3, R5 and R6 are methoxy, ethoxy, propoxy, butoxy, etc.
Preferable examples of straight or branched C1-10 alkyl in R3 is straight or branched C1-7 alkyl, e.g. methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1-ethylpropyl, hexyl, heptyl, etc.
In regard to substituents of straight or branched C1-10 alkyl in R3, examples of C1-2 alkylcarbamoyl is methylcarbamoyl, ethylcarbamoyl, etc.; examples of C2-4 dialkylcarbamoyl is dimethylcarbamoyl, methylethylcarbamoyl, diethylcarbamoyl, etc.; examples of C1-4 alkoxycarbonyl are methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 2-propoxycarbonyl, etc.; examples of C1-4 alkylcarbonyloxy are acetoxy, ethylcarbonyloxy, propylcarbonyloxy, etc., examples of amino substituted by C2-4 acyl are acetylamino, propanoylamino, etc.; examples of sulfonylamino substituted by C1-4 alkyl are methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, butylsulfonylamino, etc.; examples of C1-5 alkoxycarbonylamino are methoxycarbonylamino, ethoxycarbonylamino, propyloxycarbonylamino, butoxycarbonylamino, etc.
R11 in R3 means phenyl, pyridyl, thienyl, or furyl, and each of them may be substituted by one or more substituents. Phenyl and pyridyl are preferable, and phenyl is especially preferable. The substituents are halogen atoms, such as F, Cl, Br, etc., cyano, carbamoyl, C1-4 alkoxy, such as methoxy, ethoxy, propoxy, etc., C1-4 alkyl, such as methyl, ethyl, propyl, butyl, etc. n is integers 0-4, provided that n is integers 1-4 when R11 is phenyl. n is preferably integers 0-2, more preferably 1 or 2.
Examples of a 5 to 7 membered saturated heterocyclic ring containing one or two oxygen atoms as heteroatoms in R5 are tetrahydrofuran, oxane, 1,4-dioxane, oxepane, etc.
Preferable substituents of straight or branched C1-10 alkyl in R5 are hydroxy, its preferable number are one or more, and its preferable position is 1 or 2 (position 2 or 3 on counting from amino group of pyrimidine ring). When the substituent of straight or branched C1-10 alkyl in R5 is hydroxy, its position is preferably not the end position of the alkyl chain.
Examples of C6-10 aryl in R6 are phenyl, naphthyl, etc.
Preferable examples of straight or branched C1-10 alkyl in R9 is straight or branched C2-4 alkyl, e.g. ethyl, propyl, 1-methylethyl, butyl, etc.
Examples of C3-6 alkylene which R2 and R3 taken together form are trimethylene, tetramethylene, pentamethylene, etc. They are illustrated as following formulas (4), (5) and (6); 
Examples of C3-5 alkylene which R2 and R3 taken together form in which methylene is substituted by O atom, are oxybismethylene, oxymethyleneethylene, oxybisethylene, etc. They are illustrated as following formulas (7), (8), (9), (10), (11) and (12); 
The pyrimidine derivatives of the present invention being active ingredients as medical drugs are formed into pharmaceutically acceptable salts. As pharmaceutically acceptable salts, there are illustrated acid addition salts and base addition salts. As acid addition salts, there are illustrated inorganic acid salts, such as hydrochloride, hydrobromide, sulfate or phosphate, or organic acid salts, such as citrate, oxalate, malate, tartrate, fumarate or maleate. As base addition salts, there are inorganic base salts such as sodium salts or calcium salts, or organic base salts, such as meglumine salt, tris(hydroxymethyl)aminomethane salt. The pyrimidine derivatives of the present invention or pharmaceutically acceptable salts thereof also include solvates such as hydrates, etc.
The compounds of the formula (1) of the present invention can be prepared by the following method or according to the following method. 
wherein R1, R2 and R3 are the same as defined in the formula (1) above.
The compound (22) is prepared by reacting the compound (21) with phosphorus oxychloride. The reaction may be carried out, if necessary in the presence of a solvent. As the solvents, there are aromatic hydrocarbons such as toluene or xylene. The reaction may be carried out in the presence of a reaction promoter such as N,N-dimethylaminopyridine. The reaction temperature is selected between room temperature and reflux temperature of the solvent.
The compound (1) of the present invention can be prepared by reacting the compound (22) with the compound (23). As the solvents, there are aromatic hydrocarbons such as toluene or xylene, ethers such as tetrahydrofuran (THF) or dioxane, alcohols, such as ethanol, 2-propanol or butanol, or inert solvents such as dimethylformamide (DMF) or acetonitrile. The reaction is carried out, if necessary in the presence of an organic base such as triethylamine, or an inorganic base such as sodium carbonate or potassium carbonate. The reaction temperature is selected between for example, room temperature and reflux temperature of the solvent.
The compound (25) can be prepared by reacting the compound (24) with the compound (23). As the solvents, there are aromatic hydrocarbons such as toluene or xylene, ethers such as tetrahydrofuran (THF) or dioxane, alcohols such as ethanol, 2-propanol or butanol, or inert solvents such as dimethylformamide (DMF) or acetonitrile. The reaction may be carried out, if necessary in the presence of an organic base such as triethylamine, or an inorganic base such as sodium carbonate or potassium carbonate. The reaction temperature is selected between for example, room temperature and reflux temperature of the solvent.
The compound (1) of the present invention can be prepared by reacting the compound (25) with ammonia in a solvent. As the solvents, there are alcohols such as methanol or ethanol ethers such as dioxane or ethyleneglycol dimethyl ether. The reaction is carried out in an autoclave at room temperature to about 200xc2x0 C.
The compound (1) of the present invention can also be prepared by reacting the compound (25) with sodium azide, followed by reduction with triphenyl phosphine. The reaction with sodium azide is carried out in an inert solvent such as DMF, etc. The reaction temperature is selected from about room temperature to around the boiling point of the solvent. Reduction by triphenyl phosphine is carried out in an ether such as THF, etc. The reaction temperature is selected from about room temperature to around the boiling point of the solvent.
The compounds of the formula (1) of the present invention and intermediates for preparing them can be purified with conventional methods such as column chromatography, recrysatallization, etc. As the solvents for recrystallization there are alcohols such as methanol, ethanol or 2-propanol, ethers such as diethyl ether, esters such as ethyl acetate, aromatic hydrocarbons such as toluene, ketones such as acetone, hydrocarbons such as hexane, or a mixture thereof.
In case of carrying out above reactions, protection or deprotection techniques are, if necessary, employed. The protection or deprotection techniques are in detail described in xe2x80x9cProtecting Groups in Organic Synthesisxe2x80x9d by T. W. Greene and P. G. M. Wuts (1991), JOHN WILEY and SONS INC.
The pyrimidine derivatives of the present invention or pharmaceutically acceptable salts thereof can form solvates such as hydrates and therefore, the present invention also includes the solvates.
When the compounds of the present invention have an asymmetric carbon atom(s), optical isomers exist and therefore, a mixture thereof and an isolated optical isomer are included in the compounds of the present invention. In order to purify such an optical isomer, optical resolution is employed.
As to to optical resolution, the compounds of the present invention or intermediates thereof can be formed salts with an optically active acid (e.g. monocarboxylic acid such as mandelic acid, N-benzyloxyalanine or lactic acid, dicarboxylic acid such as tartaric acid, O-diisopropylidene tartaric acid or malic acid, or sulfonic acids such as campher-sulfonic acid, bromocampher-sulfonic acid) in an inert solvent (e.g. alcohols such as methanol, ethanol or 2-propanol, ethers such as diethyl ether, esters such as ethyl acetate, aromatic hydrocarbons such as toluene, acetonitrile or a mixture thereof).
When the compounds of the present invention or intermediates thereof have an acidic substituent such as carboxy group, etc., they can be formed salts with an optically active amine (e.g. an organic amine such as xcex1-phenethylamine, quinine, quinidine, cinchonidine, cinchonine, strychnine, etc.), too.
The temperature forming salts is from room temperature to the boiling point of the solvent. In order to increase the optical purity of the compound, the temperature is preferably raised once to around the boiling point of the solvent. The yield can be increased, if necessary by cooling the solvent before filtering a precipitated salt. The amount of an optically active acid or amine is about 0.5-2.0 equimoles to the substrate, preferably about 1 equimole. If necessary, the crystals are recrystallized in an inert solvent (e.g. alcohols such as methanol, ethanol or 2-propanol, ethers such as diethyl ether, esters such as ethyl acetate, aromatic hydrocarbons such as toluene, acetonitrile or a mixture thereof) to be obtainable an optically active salt with highly optical purity. The obtained salt, if necessary is treated in the conventional manner with an acid or a base to obtain a free compound.
The pyrimidine derivatives of the present invention can be orally or parenterally administered. In case of oral administration, the compound is administered in the conventional administration form. In case of parenteral administration, the compound can be administered in a topical administration forms, injections, transdermal application forms or nasal application forms. Preparations for oral or rectal administration include for example, capsules, tablets, pills, powders, cashes, suppositories, solutions, etc. Injections include for example, sterilized solutions or emulsions, etc. Topical administration preparations include, for example creams, ointments, lotions, transdermal preparations (usual paches, matrixs), etc.
The above preparations are prepared with pharmaceutically acceptable fillers and additives by the conventional method. Pharmaceutically acceptable fillers and additives include carriers, binders, flavors, buffering agents, viscosity-increasing agents, coloring agents, stabilizing agents, emulsifiers, dispersing agents, suspending agents, preservatives, etc.
Pharmaceutically acceptable carriers include, for example magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethyl cellulose, wax (lower melting point), cacao butter, etc. Capsules can be prepared by putting the compound of the present invention with pharmaceutically acceptable carriers. The compound of the present invention is mixed with pharmaceutically acceptable fillers and the mixture is put into capsules, or the compound without any filler is put into capsules. Caches can be prepared by the same method as the capsules.
Solutions for injection include, for example solutions, suspensions, emulsions, etc. such as an aqueous solution, water-propylene glycol solution. The solution may contain water and can be prepared in propylene glycol or/and propylene glycol solution. The solutions suitable for oral administration can be prepared by adding the compound of the present invention into water and if necessary, adding a coloring agent, a flavor, a stabilizing agent, a sweetening, a solubilizing agent, a viscosity-increasing agent, etc. Also the solutions suitable for oral administration can be prepared can be prepared by adding the compound of the present invention and a dispersing agent into water to make viscositic solutions. The viscosity-increasing agents include, for example natural or synthetic gum, resin, methylcellulose, sodium carboxymethyl cellulose, or known emulsifiers.
The preparations for topical administration include for example above mentioned solutions, creams, aerosols, sprays, powders, lotions, ointments, etc. The preparations for topical administration can be prepared by mixing the compound of the present invention, pharmaceutically acceptable diluents and carriers conventionally used. Creams and ointments can be prepared, for example by mixing aqueous or oil bases and viscosity-increasing agents and/or gelating agents. The bases include, for example water, liquid paraffin, plant oil (peanut oil, castor oil), etc. The viscosity-increasing agents include, for example soft paraffin, aluminum stearate, cetostearyl alcohol, propylene glycol, polyethylene glycol, lanolin, hydrogenated lanolin, bees wax, etc. The lotions can be prepared by mixing aqueous or oil bases, and one or more pharmaceutically acceptable stabilizing agents, suspending agents, emulsifiers, dispersing agents, viscosity-increasing agents, coloring agents, flavors, etc.
The powders are prepared with pharmaceutically acceptable powder bases. The bases are talc, lactose, starch, etc. Drops can be prepared with aqueous or non-aqueous bases and one or more pharmaceutically acceptable dispersing agents, suspending agents, solbilizing agents, etc.
The preparations for topical administration may contain, if necessary preservatives, such as hydroxy benzoic acid methyl ester, hydroxy benzoic acid propyl ester, chloro cresol, benzalkonium chloride, and antibacterial agents.
Liquids for spray, powders or drops containing the compound of the present invention can be nasally administered.
Dose and number of administration vary with a disease to be treated, age, body weight, route of administration. In case of oral administration, an active ingredient is administered to an adult generally about 1-500 mg per day, preferably about 5-100 mg, once or several times. In case of injections, an active ingredient is administered generally about 0.1-300 mg per day, preferably about 1-100 mg, once or several times.